Bismuth hydroxylates of polyhydroxydicarboxylic acid salts



Patented Feb. 18, 1941 UNITED STATES BISP/IUTH HYDROXYLATES OF POLYHY- DROXYDICARBOXYLIC ACID SALTS Clarence 1W. Sondern and George Doak, Kansas City, Mo., assignors to George A. Brcon & Company, Inc. tion of Missouri Kansas City, Mo., a corpora- N Drawing. Application-May 15, 1937, Serial No. 142,806

, Claims;

This invention relates to organic bismuth compounds of therapeutical value, and with regard to certain more specific features, to bismuth compounds of certain polyhydroxydicarboxylic acids.

Among the several objects of the invention may be noted theprovision of bismuth compounds of certain polyhydroxydicarboxylic acids which are soluble in water, and which, in water solution, have a hydrogen ion concentration substantially within the range found in human body tissue fluids, said compounds being thereby adapted for parenteral injection in the treatment of certain contagious diseases, especially those caused by trypanosomes and spirochetes, without causing substantial pain or irritation at the site of the injection; and the provision of methods of preparing bismuth compounds of the class described. Other objects will be in part obvious and in part pointed out hereinafter.

The invention accordingly comprises the elements and combinations of elements, steps and sequence of steps, and features of composition and synthesis, which willbe exemplified in the products and processes hereinafter described, and the scope of the application of which will be indicated in the following claims.

Compounds of bismuth with certain polyhydroxy acids and their alkali salts have been known for many years and have been used extensively inmeclicine. The vastmajority of these compounds, however, are insoluble in water at hydrogen ion concentrations within the range found in body tissue fluids. Since these compounds are primarily intended to. be used for intramuscular injection, this insolubility constitutes a decided disadvantage, as it is necessary to prepare either strongly alkaline or strongly acidic solution for injections, and it is well known that the injection of strongly alkaline or acidic solutions produces pain and irritation at the site of the injection.

It has been discovered by the present inventors that certain bismuth compounds of polyhydroxv.. dicarboxylic acids, hereinafter more accuratelv to be defined, are soluble in water and have a hydrogen ion concentration, in water solution, approximately within the range found in body tissue fluids. Such solutions represent a distinct ad- Vance in bismuth therapy, since they can be injected Without causing the disagreeable painand irritation associated with the heretofore prepared acidic or alkaline bismuth salt solutions.

Generally speaking, the compounds coming within the scope of the present invention appear to have approximately the following empirical formula;

C 0 OM HM K MM in whichMf and M represent the same or different substituents selected from the group consisting of hydrogen, the alkali metals, ammonium, and the alkaline salt forming amines, and y is within the range of 1 to 3.

Principal among the compounds corresponding to the foregoing formula are the alkali salts of bismuthyl tetrahydroxyadipic (or saccharic) acids, such as potassium (ii-bismuthyl saccharate, sodium di-bismuthyl saccharate, sodium potassium (ii-bismuthyl saccharate, and other alkali salts of bismuthyl saccharic acids.

The bismuthyl salts of these polyhydroxydican boxylic acids herein described diifer materially from those produced from such polyhydroxy acids as tartaric, gluconic, and like acids, in that their aqueous solution can readily be adjusted to pH values of approximately 7.0 to 7.4 without precipitation. This could not have been forseen by comparison of the structure of saccharic acids, and other similar polyhydroxydicarboxylic acids with the structure of such other polyhydroxy acids as tartaric, gluconic, and the like. I

From the structure assigned to other bismuth derivatives of polyhydroxy acids itv might be assumed that the bismuthyl saccharates, for example, possess. the following general formula:

OH OH in which M and M" have the same significance as in the first formula set forth.

The bismuth analyses of the compounds that we have prepared agree quite satisfactorily with such a formula; However; in view of certain properties of these compounds and in further view of the fact that there is but little experimental proof for the foregoing type of formula, either in the case of saccharic acid or other polyhydroxy acid compounds of bismuth, we prefer to regard the compounds that we have isolated as complex alkali bismuth salts of polyhydroxydicarboxylic acids, the exact structural formulae of which are not at present known.

The compoundsof the present invention are in general obtainable by a'reaction between a selected polyhydroxydicarboxylic acid or one of its soluble salts, in an alkaline solution, with a bismuth salt such as bismuth nitrate, or bismuth oxide or hydroxide. Purification of the compound is then effected by repeated precipitations with alcohol from aqueous solutions.

Among the polyhydroxydicarboxylic acids that we have proved to be suitable for the purposes of the present invention are the following tetrahydroxyadipic acids: Dextro-saccharic acid, laevo-saccharic acid, mucic acid, manno-saccharic acid, and idosaccharic acid.

It is to be understood that the formation of complex compounds of bismuth with polyhydroxydicarboxylic acids and their alkali salts yielding aqueous stable solutions within a pH range of approximately 7.0 to 7.4, is not limited to compounds wherein the bismuth is contained in stoichiometric proportions. Suitable complex compounds are likewise obtainable when employing a quantity of the bismuth compound which is above or below 2 mols of bismuth for each mol of polyhydroxydicarboxylic acid.

The following examples are intended to illustrate the general method by which the compounds of the present invention may be obtained, but are not to be considered as limiting the invention to the compounds therein described:

Ewample I a Bismuth hydroxide, freshly precipitated from 48.5 grams (one-tenth mol) of bismuth nitrate, Bi(NO3) 3.5Hz0, with ammonium hydroxide, and Washed free from nitrates with distilled water, was suspened in distilled water and added slowly to a solution containing 10.5 grams (one-twentieth mol) of dextro-saccharic acid and 10.25 grams of potassium hydroxide in 200 cc. of water. The solution was mechanically stirred during the entire operation. The resulting solution was yellow in color and alkaline to litmus. After filtering, an equal volume of 95% ethylalcohol was added. This caused the rapid precipitation of a gummy yellow product. The supernatant liquid was poured off and the gummy yellow 45 precipitate dissolved in water. The solution was then again treated with ethyl alcohol to again form a precipitate. After three such precipitations with ethyl alcohol a white granular substance was obtained. It was filtered, washed with 50% ethyl alcohol, then 95% ethyl alcohol, and finally with ether. The compound was then dried in a vacuum over calcium chloride.

The resultant compound is freely soluble in water. Analysis by precipitation of the bismuth 55 with hydrogen sulphide showed that the compound contained 56.75% bismuth, agreeing with the formula:

KOOCCH(l3H-CH(lJH-COOK tion was filtered and precipitated three times with ethyl alcohol as in Example Land then the precipitate was washed and dried. The resultant compound contained 59.1% of bismuth, whereas the theoretical bismuth content for the compound:

is 58.2%. Sodium and potassium analyses revealed that there were slightly less sodium and potassium than that required by the above formula.

Example II I l3i 113i OH OH for which the theoretical bismuth and sodium values are 61.47% and 3.38%, respectively.

In View of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in carrying out the above compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

We claim:

1. A compound selected from the group consisting of the alkali metal, ammonium and amine salts of a polyhydroxydicarboxylic acid containing a carbon chain of six carbon atoms, and wherein two atoms of bismuth are indirectly linked to non-carboxylic carbon atoms of said chain, said compound being readily soluble in water and forming solutions stable at a pH value of approximately 7.0 to approximately 7.4.

2. A compound having substantially the following composition:

COOM

(CHO)lBiz(OH)2 C O OM in which M and M are selected from the group consisting of hydrogen, the alkali metals, ammonium and the amines, said compound being readily soluble in water to form a stable solution having a pH value of approximately 7.0 to approximately 7.4.

a 3. The di-potassium salt of di-bismuthyl saccharic acid.

4. The sodium-potassium salt of di-bismuthyl saccharic acid.

5. The acid sodium salt of di-bismuthyl saccharic acid.

CLARENCE W. SONDERN. GEORGE 0. DOAK. 

